Central Nervous System Infections Clinical Aspects

Imran I Ali M.D. Professor of Neurology University of Toledo College of Medicine

CNS Infections
Objectives Describe the epidemiology/ pathogenesis/ microbiology/ clinical presentation/diagnosis/ basic treatment of common CNS infections

CNS Infections
Brain
Acute Bacterial Meningitis
S. Pneumoniae

Spinal Cord
Epidural Abscess Viral myelitis

Subdural Empyema Brain abscess Viral Meningitis Viral Encephalitis

HSE HIV

CNS Anatomy
To understand central nervous system infections - pathogenesis, presentations - it is necessary to recall the basics of CNS anatomy brain and spinal cord are surrounded by the leptomeninges (pia mater and arachnoid) pia mater is continuous and tightly adherent to the brain arachnoid encloses parenchyma and pia mater loosely

CNS Anatomy
Cerebral spinal fluid (CSF) - located in the space between the pia mater and the arachnoid mater (a.k.a. - the subarachnoid space) secretion of CSF mostly by cells in the choroid plexus (in the lateral, 3rd, 4th ventricle)

CNS Anatomy
CSF
Composition: derived from blood plasma
Small amount of protein ( <45 mg/dl) Less sugar (> 50% serum), less specific gravity, and more chloride (n-118-132) than blood plasma Total amount is 140-150 cc on average Opening pressure is approximately 8-16 cm water (80-160 mm), > 20 cm water is abnormal!

CNS Anatomy
Dura mater Adherent to the periosteum and skull except for four rigid septa falx cerebri, falx cerebelli, tentorium cerebelli, diaphragma selli Brain sits on the cranial fossa Anterior fossa is actually the roof of the frontal and ethmoid sinuses

CNS Anatomy
Blood -Brain barrier Capillaries in the CNS have tight junctions (no fenestrations in general) and are surrounded by the foot processes of nearby astrocytes this forms the relatively impermeable blood brain barrier Blood brain barrier does not generally allow large molecules to enter CNS by diffusion

CNS Infections
CNS is well protected- difficult for organisms to penetrate into brain (also difficult for good things like antibiotics, complement, and antibodies as well) CNS is a tightly enclosed space and so even very small amounts of organisms causing inflammation (edema) can have devastating consequences

CNS Infections CNS infections are grouped by anatomical location Encephalitis - infection of brain parenchyma Meningitis - infection of leptomeninges Myelitis - infection of spinal cord tissue Neuritis - infection of peripheral nerves Organisms enter CNS via bloodstream, neuronal pathways, or direct inoculation

Acute Bacterial Meningitis Meningitis - inflammation of the meninges if the brain parenchyma is also involved, it is called meningoencephalitis if brain and spinal cord tissue are also involved, it is meningoencephalomyelitis Acute bacterial meningitis infection of meninges due to bacteria with clinical presentation within 24 - 48 hours sine qua non is CSF leukocytosis

Acute Bacterial Meningitis Epidemiology and Etiology 3 cases per 100,000 in US rate is over 15x higher in underdeveloped countries epidemics are also common in addition to the high endemic rate Common organisms are S. pneumoniae, N. meningitidis, H. influenzae, L. monocytogenes

Acute Bacterial Meningitis 0 - 4 weeks : Group B streptococcus (S. agalactiae), E. coli, L. monocytogenes < 18 y/o: H. flu (type b greatly decreased, other strains increasing), N. meningitidis, S pneumoniae 18 - 50 y/o: N. meningitidis, S pneumoniae >50 y/o: N. meningitidis, S pneumoniae, L. monocytogenes, GNR

Epidemiology of ABM

Risk Factors in the Elderly

Acute Bacterial Meningitis

H. influenza Type b vaccine has greatly decreased the rate of H. flu meningitis but invasive disease due to other encapsulated strains such as type f are increasing In patients >5 yo, meningitis may be associated with sinusitis, otitis, epiglottitis, pneumonia Predisposing conditions: DM, alcoholism, asplenia, CSF leak, hypogammaglobulinemia

Acute Bacterial Meningitis N. meningiditis Serotypes A,B,C, W135, and Y commonly associated with meningitis Serotype B causes >50% of infections Vaccine is active against A, C, W135, and Y Terminal complement deficiencies are associated with increase in attack rate and decrease in fatality rate

Acute Bacterial Meningitis S. pneumoniae # 1 cause of meningitis in 18 - 50 yo often associated with URI/LRTI or endocarditis predisposing conditions: DM, alcoholism, asplenia, CSF leak, hypogammaglobulinemia vaccine covers most common serotypes associated with meningitis

Acute Bacterial Meningitis

L. monocytogenes
Causes 2 - 3% of cases of meningitis but is seen in neonates, pregnant women, elderly, immunocompromised Cephalosporins are not active against Listeria and vancomycin is not reliably effective Ampicillin or Trimethoprim-sulfa are treatments of choice

ACUTE BACTERIAL MENINGITIS

Consider in patients with fever and any neurologic symptoms/ cerebral dysfunction Typical presentation-headache, fever, lethargy, confusion, vomiting, stiff neck - but presentation may be variable < 80% nuchal rigidity, Kernigs or Brudzinskis signs Papilledema: <1% of patients

Acute Bacterial Meningitis

Kernigss sign patient lies supine with thigh and knee flexed leg is passively extended and this is resisted with meningeal inflammation Brudzinskis sign passive flexion of the neck causes passive flexion of pelvis/hips

Acute Bacterial Meningitis CID July 2002 :35; 46-52. Thomas, et al. The diagnostic accuracy of Kernigs sign, Brudzinskis sign, and Nuchal Rigidity in Adults with suspected meningitis.
Prospective study of meningeal signs prior to LP
Kernigs sign and Brudzinskis sign - sensitivity 5%: positive predictive value - 27% nuchal rigidity - sensitivity 30%: positive predictive value - 26%

Acute Bacterial Meningitis

Acute Bacterial Meningitis CSF examination essential Contraindications to lumbar puncture increased intracranial pressure platelet count <40,000 or prolonged pt severe scoliosis infected site over lumbar spine these are relative contraindications only

Acute Bacterial Meningitis

CSF EXAMINATION Need to order WBC with differential Glucose Protein Gram stain and culture Need 4-8 cc Always take more than you need! CSF EXAMINATION Special Studies
Cytology Cryptococcal Antigen and India Ink VDRL AFB & Fungal Smear & CS Viral Studies ?Latex agglutination

Acute Bacterial Meningitis Bacterial meningitis partially tx WBC >1000 with >60% PMNs Glucose often < 45 Protein may be increased Gram stain and culture positive 60 - 65% Latex agglutination may be helpful here Oral ATB (low dose) usually leaves CSF

abnormal, especially glucose

Acute Bacterial Meningitis Treatment (begin within 30 minutes)

Needs to cover the most commonly encountered pathogens: treat for 10 -14 days Ceftriaxone 2 grams iv bid + Vancomycin if >2% community incidence of high level S.pneumoniae resistance + Ampicillin 4 grams q6 hours if patient > 50 or immunocompromised Dexamethasone used in children -lactam anaphylaxis - Tmp-smx + chloramphenicol.

Acute Bacterial Meningitis Dexamethasone in adults 301 patients with bacterial meningitis
157 received Dexamethasone with ATB or 15 minutes prior 144 ATB alone
mortality and adverse outcome (Glasgow Outcome Scale) improved with Dexamethasone, especially in the patient subset with pneumococcal meningitis sensitive to PCN NEJM 2002: 347: 20 : 1549 - 1556

Complications
Raised intracranial pressure Seizures Hearing loss Hydrocephalus Subdural Empyema Cerebral Infarction Cognitive Impairment

 Death

Acute Viral Meningitis Viral meningitis is often referred to as aseptic meningitis meningitis without bacterial etiology generally means viral etiology Enteroviruses cause 80-85% of cases of viral meningitis arbovirus, herpes virus, and HIV are also common causes of aseptic meningitis

Acute Viral Meningitis Pathophysiology Mucosal colonization -->viremia --> BBB crosses by virus (or may travel along nerve endings) --> viral entry into subarachnoid space --> spread of virus in CSF --> inflammatory response specific for the virus and consisting of lymphocytes begins: T-cell response needed to clear CSF

Acute Viral Meningitis

Clinical manifestations Enterovirus meningitis in kids > 2 weeks old sudden onset of fever, severe frontal headache, photophobia, nuchal rigidity and myalgias, vomiting, diarrhea, anorexia, cough, sore throat usually occurs in the summer months may also be associated with recognizable enteroviral syndromes (eg - classic rash of handfoot-and-mouth disease, the painful mouth vesicles of herpangina)

Acute Viral Meningitis Clinical manifestations Initial episode of HSV 2 infection often associated with aseptic meningitis and signs of genital tract infection Initial episode of HIV infection may also be associated with aseptic meningitis

Acute Viral Meningitis Diagnosis LP with <1000cells/mm, usually lymphs, with mildly elevated protein and normal glucose is common difficult to culture viruses out of CSF usually but it can be done PCR of HSV on CSF is available and very sensitive and specific

Acute Viral Meningitis Viral (aseptic) meningitis WBC usually <1000 and almost always < 3000. up to 10% of patients may have PMN predominance Glucose and protein usually normal (notable exceptions- HSV, LCM, mumps, EEE) Gram stain and culture negative

Acute Viral Meningitis Treatment Enterovirus: Consider use of IVIG if patient is extremely ill Herpes virus: Acyclovir HIV: Consider triple drug therapy

Chronic Meningitis
Definition Neurologic abnormalities or CSF abnormalities of > 4 weeks duration Etiology Infections: TB, Nocardia, Cryptococcus, Syphilis, Lyme Disease Noninfectious diseases: Behcets, Meningeal Carcinomatosis, Sarcoidosis

Chronic Meningitis
Clinical Manifestations Often insidious onset of symptoms which wax and wane over weeks but with gradual neurologic decline Cranial neuropathies Focal neurological signs such as weakness, ataxia, sensory loss

Chronic Meningitis
Diagnosis and Treatment Diagnostic workup is very difficult and is guided by a thorough history and physical exam plus lumbar puncture(s) Treatment is generally not empiric but is guided by the most likely initial diagnosis if the patient is critically ill or preferably by a confirmed diagnosis

Chronic Meningitis
Fungal WBC <500 glucose normal or low protein >60 need special smears and cultures Tuberculosis WBC < 1,000 Glucose <45 Protein>> 100 AFB smear and culture positive more than >85% need to examine 10cc centrifuged fluid for > 1 hour

Chronic Meningitis

A 36 year old with 3 week history of progressive gait disorder, weakness and multiple cranial neuropathies.

TB Meningitis

A 12 year old immigrant from South Asia with chronic cough and headaches. Examination shows bilateral sixth nerve paralysis.

Intracranial Abscess
Definition: abscess in brain parenchyma May or may not be associated with meningeal involvement From contiguous foci - 50% From hematogenous dissemination - 25% From direct inoculation - 10% Primary abscess - 15%

Intracranial Abscess Pathogenesis - site of abscess gives a clue to its origin Frontal lobe: sinuses, teeth, direct inoculation Temporal lobe: otitis, mastoiditis, sphenoid sinusitis Cerebellum: otitis, mastoiditis MCA circulation - hematogenous source (eglung abscess, endocarditis) Beneath area of a wound - direct inoculation

Intracranial Abscess
4 stages of abscess formation early cerebritis 1 - 3 days late cerebritis 4 - 9 days early capsule 10 - 13 days late capsule > 14 days

Intracranial Abscess
Bacteriology
Otitis/mastoiditis - Strep, Bacteroides, GNR Sinusitis - same as otitis + S. aureus Teeth - Fusobacterium, anaerobes, strep Wound - staph, strep, GNR, Clostridium Endocarditis - staph or strep Lung - actinomyces, anaerobes, strep, fusobacterium, nocardia Immunocompromised - toxoplasmosis, fungi, GNR, nocardia

Intracranial Abscess
Clinical manifestations Space occupying lesion --> headache, N/V, seizures, mental status change, focal neurologic deficit deficit depends on location -cerebellar abscess may have ataxia, temporal lobe may have visual field defect, etc generally < 50% have fever with

presentation

Intracranial Abscess
Diagnosis MRI or CT scan with contrast are diagnostic modalities of choice MRI is very sensitive Avoid LP

Intracranial Abscess

Intracranial Abscess
Treatment Surgical drainage and management of increased ICP almost always required Search for source Culture abscess for bacteria, fungi, mycobacteria and obtain immediate gram stain, AFB stain and fungal smears to help guide therapy Empiric ATB - metronidazole + 3rd gen ceph+ nafcillin or vancomycin

Encephalitis Encephalitis means inflammation of the brain - it is characterized by alterations in consciousness many non-infectious diseases can be associated with encephalitis (eg- drug reactions, vasculitis) in general, infectious encephalitis is due to viral infection, less commonly

bacterial, fungal, or tubercular infection

Encephalitis -Common Viral Causes

Herpesviruses - HSV 1 and 2, VZV (only treatable form of encephalitis) West Nile HIV Togaviruses - cause EEE (eastern equine encephalitis), WEE (western EE), and VEE (Venezuelan EE) Flaviviruses - St. Louis encephalitis, West Nile virus Enteroviruses (e.g. poliovirus) Rhabdovirus rabies Paramyxoviruses measles

Encephalitis
Pathophysiology Pathogens enter brain parenchyema in several ways Hematogenous - occurs for many viral infections, rickettsia, bacteria, fungi, and TB Retrograde peripheral transport - rabies, varicella Exposed olfactory nerves - definitely the route of entry for Naegleria and Acanthamoeba but in experimental animals is also route of entry for most viruses

Encephalitis Clinical Manifestations Classic presentation is altered mental status and personality changes, decreases level of consciousness, focal neurologic findings, and seizures

Encephalitis Diagnosis EEG often has a characteristic pattern MRI in HSV encephalitis shows temporal lobe involvement LP often with mild pleocytosis PCR for HSV is diagnostic

Encephalitis Treatment Intravenous Acyclovir is effective treatment for encephalitis caused by HSV1/2 and VZV. Ganciclovir and Foscarnet for CMV HAART for HIV

West Nile Encephalitis

A 79 year old with headaches, progressive weakness and encephalopathy.

HIV Encephalitis

A 32 year old with poor memory, weakness and inability to comprehend.

Neurological Complications of HIV

Meningitis acute or chronic

Encephalopathy Vacuolar myelopathy Peripheral neuropathy

distal symmetric polyneuropathy Mononeuritis multiplex

Myopathy

Secondary Involvement
Opportunistic infections
Toxoplasmosis, Cryptococcus meningitis, CMV, PML

Neoplasms
Lymphoma

Vascular Drug toxicity Nutritional and metabolic

PML

CNS Lymphoma

Myelitis- Infectious Causes Highlights

Herpes Virus
VZV

Bacterial
Lyme, Syphilis

Picornavirus
Enteroviruses, Polio

Fungal
Aspergillus

Flaviviruses
West Nile, Japanese B, St. Louis

Parasitic
Schistosomiasis

Retrovirus
HIV, HTLV-1

Clinical Presentation
Acute to sub acute onset Weakness involving arms and/or legs Numbness and sensory loss Incontinence (bowel and/or bladder)

Subdural Empyema
Definition - pyogenic infection of space between the dura and arachnoid Subdural space is crossed by numerous small veins (emissary vessels) and divided into several anatomic compartments by the falx cerebri, tentorium cerebelli, and base of the brain @ 20 % of all intracranial infections

Subdural Empyema
Organisms reach subdural space through emissary vessels or direct extension of osteomyelitis of the skull (as a sequalae of associated epidural abscess) Source of empyema 50 - 80 % frontal or ethmoid sinusitis 10-20% otitis media/mastoiditis 5% hematogenous dissemination of infection

Subdural Empyema
Bacteriology aerobic streptococci, staphylococci, S. pneumoniae, H. influenzae, anaerobes, other gram - negative organisms, polymicrobic infections are common Epidemiology 4:1 males to females usually 2nd and 3rd decades of life

Subdural Empyema
Clinical Manifestations Acts like a rapidly expanding mass lesion Fever, focal headache that later generalizes, vomiting, altered mental status Focal neurologic signs appear then spread and expand rapidly to include hemiparesis, seizures Due to rapid spread < 50% have papilledema Occasionally patients progress neurologically in weeks, rather than hours

Subdural Empyema
Diagnosis MRI is diagnostic and very sensitive CT scan will miss some subdural empyemas CSF + in 14% of cases but LP is contraindicated

Subdural Empyema
Treatment Neurosurgery for burr holes or craniotomy Aggressive management of increased ICP including use of dexamethasone Culture of empyema fluid May need simultaneous debridement of sinuses, mastiod, or ear

Subdural Empyema
Treatment Antibiotics indicated for a minimum of three weeks need to cover anaerobes, GNR, GPC Metronidazole + Ceftriaxone + Nafcillin or Vancomycin would be good empiric therapy pending culture results Prognosis 75% mortality if comatose, otherwise @ 15% 42% of survivors develop seizures

Epidural Abscess
Abscess located between bone and the dura mater Intracranial epidural abscess generally spills over into the subdural space and forms an associated subdural empyema as well (81% of the time) etiology/pathogenesis/microbiology/ diagnosis/therapy same as for subdural empyema

Epidural Abscess
Intracranial epidural abscess Inflammation of the face or scalp may be present otherwise clinical manifestations are the same Spinal epidural abscess is different from intracranial epidural abscess in spinal canal, dura mater is not adherent to the vertebra but epidural space is a distinct fat filled anatomic space without emissary vessels

Spinal Epidural Abscess

Spinal epidural abscess Spinal canal anatomy allows easy longitudinal but not subdural spread Neurological emergency! Etiology Bacteria enter epidural spinal space by direct extension from vertebral osteomyelitis or hematogenous dissemination

Spinal Epidural Abscess

Less often polymicrobial than intracranial epidural abscess S aureus 60 -90% and often the sole pathogen followed by streptococci, anaerobes, and gram-negative rods Abscess at time of diagnosis usually covers 4 - 5 vertebra but may extend the whole length of spine

Spinal Epidural Abscess

Clinical manifestations Focal vertebral pain develops first, followed by radiculopathy, then motor and/or sensory deficits (sphincter function if lumbar location), and finally increasing paralysis Patients may (or may not) have fever and appear quite ill Time course of evolution of clinical features can be a few hours to days/weeks

Spinal Epidural Abscess

Clinical manifestations
Often see nuchal rigidity and severe focal tenderness

Diagnosis
MRI is diagnostic modality of choice Myelogram (injection of radio-opaque dye into arachnoid space) can be used as well to visualize the cord and look for compression (not preferred) blood cultures are often positive, SED usually elevated

Spinal Epidural Abscess

Treatment Immediate surgical drainage traditional teaching
Case reports of recovery in selected patients with antibiotics alone

Cover S. aureus, GNR, and anaerobes pending culture results Vancomycin +3rd gen ceph + metronidazole Prognosis if treated prior to paralysis/ very poor if paralysis present >24 hours

Recap